Docking-based development of purine-like inhibitors of cyclin-dependent kinase-2.

The cell division cycle is controlled by cyclin-dependent kinases (cdk), which consist of a catalytic subunit (cdk1-cdk8) and a regulatory subunit (cyclin A-H). Purine-like inhibitors of cyclin-dependent kinases have recently been found to be of potential use as anticancer drugs. Rigid and flexible docking techniques were used for analysis of binding mode and design of new inhibitors. X-ray structures of three (ATP, olomoucine, roscovitine) cdk2 complexes were available at the beginning of the study and were used to optimize the docking parameters. The new potential inhibitors were then docked into the cdk2 enzyme, and the enzyme/inhibitor interaction energies were calculated and tested against the assayed activities of cdk1 (37 compounds) and cdk2 (9 compounds). A significant rank correlation between the activity and the rigid docking interaction energy has been found. This implies that (i) the rigid docking can be used as a tool for qualitative prediction of activity and (ii) values obtained by the rigid docking technique into the cdk2 active site can also be used for the prediction of cdk1 activity. While the resulting geometries obtained by the rigid docking are in good agreement with the X-ray data, the flexible docking did not always produce the same inhibitor conformation as that found in the crystal.

[1]  S H Kim,et al.  Inhibition of cyclin-dependent kinases by purine analogues: crystal structure of human cdk2 complexed with roscovitine. , 1997, European journal of biochemistry.

[2]  C. W. Parker,et al.  Inhibitors of two enzymes which metabolize cytokinins , 1986 .

[3]  L. Meijer,et al.  ATP-site directed inhibitors of cyclin-dependent kinases. , 1999, Current medicinal chemistry.

[4]  D. Goodsell,et al.  Automated docking of substrates to proteins by simulated annealing , 1990, Proteins.

[5]  L Meijer,et al.  Discovery and initial characterization of the paullones, a novel class of small-molecule inhibitors of cyclin-dependent kinases. , 1999, Cancer research.

[6]  U Pindur,et al.  Advances in indolo[2,3-a]carbazole chemistry: design and synthesis of protein kinase C and topoisomerase I inhibitors. , 1999, Current medicinal chemistry.

[7]  P. Furet,et al.  2,6,9-trisubstituted purines: optimization towards highly potent and selective CDK1 inhibitors. , 1999, Bioorganic & medicinal chemistry letters.

[8]  C. W. Parker,et al.  Substituted xanthines and cytokinin analogues as inhibitors of cytokinin N-glucosylation , 1991 .

[9]  L Meijer,et al.  Multiple modes of ligand recognition: Crystal structures of cyclin‐dependent protein kinase 2 in complex with ATP and two inhibitors, olomoucine and isopentenyladenine , 1995, Proteins.

[10]  Todd J. A. Ewing,et al.  Critical evaluation of search algorithms for automated molecular docking and database screening , 1997 .

[11]  E. Clark,et al.  DIACYL DERIVATIVES OF ORTHO-HYDROXYBENZYLAMINE , 1923 .

[12]  J. Wu,et al.  Characterization of novel inhibitors of cyclin-dependent kinases. , 1999, Biochemical and biophysical research communications.

[13]  Doris Marko,et al.  Indirubin, the active constituent of a Chinese antileukaemia medicine, inhibits cyclin-dependent kinases , 1999, Nature Cell Biology.

[14]  E. Sausville,et al.  Potent inhibition of CDC2 kinase activity by the flavonoid L86-8275. , 1994, Biochemical and biophysical research communications.

[15]  L. Meijer,et al.  Cytokinin-derived cyclin-dependent kinase inhibitors: synthesis and cdc2 inhibitory activity of olomoucine and related compounds. , 1997, Journal of medicinal chemistry.

[16]  Structure-based inhibitor design for CDK2, a cell cycle controlling protein kinase , 1998 .

[17]  T. Lybrand.  Ligand-protein docking and rational drug design. , 1995, Current Opinion in Structural Biology.